1910-41-4Relevant academic research and scientific papers
Catalytic reduction of redox-active co-factors and proteins by dihydrogen with Sephadex supported platinum clusters as catalysts
Bhaduri, Sumit,Sharma, Krishna
, p. 207 - 208 (1996)
The platinum carbonyl cluster [Pt15(CO)30]2-, anchored onto QAE-SEPHADEX anion exchanger, is an effective catalyst for the reduction of flavin co-factors, lipoamide dehydrogenase and CytCox.
E. coli Nickel-Iron Hydrogenase 1 Catalyses Non-native Reduction of Flavins: Demonstration for Alkene Hydrogenation by Old Yellow Enzyme Ene-reductases**
Cleary, Sarah E.,Joseph Srinivasan, Shiny,Paul, Caroline E.,Ramirez, Miguel A.,Reeve, Holly A.,Vincent, Kylie A.
, p. 13824 - 13828 (2021)
A new activity for the [NiFe] uptake hydrogenase 1 of Escherichia coli (Hyd1) is presented. Direct reduction of biological flavin cofactors FMN and FAD is achieved using H2 as a simple, completely atom-economical reductant. The robust nature of
Methylene Homologues of Artemisone: An Unexpected Structure–Activity Relationship and a Possible Implication for the Design of C10-Substituted Artemisinins
Wu, Yuet,Wu, Ronald Wai Kung,Cheu, Kwan Wing,Williams, Ian D.,Krishna, Sanjeev,Slavic, Ksenija,Gravett, Andrew M.,Liu, Wai M.,Wong, Ho Ning,Haynes, Richard K.
, p. 1469 - 1479 (2016/07/16)
We sought to establish if methylene homologues of artemisone are biologically more active and more stable than artemisone. The analogy is drawn with the conversion of natural O- and N-glycosides into more stable C-glycosides that may possess enhanced biological activities and stabilities. Dihydroartemisinin was converted into 10β-cyano-10-deoxyartemisinin that was hydrolyzed to the α-primary amide. Reduction of the β-cyanide and the α-amide provided the respective methylamine epimers that upon treatment with divinyl sulfone gave the β- and α-methylene homologues, respectively, of artemisone. Surprisingly, the compounds were less active in vitro than artemisone against P. falciparum and displayed no appreciable activity against A549, HCT116, and MCF7 tumor cell lines. This loss in activity may be rationalized in terms of one model for the mechanism of action of artemisinins, namely the cofactor model, wherein the presence of a leaving group at C10 assists in driving hydride transfer from reduced flavin cofactors to the peroxide during perturbation of intracellular redox homeostasis by artemisinins. It is noted that the carba analogue of artemether is less active in vitro than the O-glycoside parent toward P. falciparum, although extrapolation of such activity differences to other artemisinins at this stage is not possible. However, literature data coupled with the leaving group rationale suggest that artemisinins bearing an amino group attached directly to C10 are optimal compounds.
Reactions of Antimalarial Peroxides with Each of Leucomethylene Blue and Dihydroflavins: Flavin Reductase and the Cofactor Model Exemplified
Haynes, Richard K.,Cheu, Kwan-Wing,Tang, Maggie Mei-Ki,Chen, Min-Jiao,Guo, Zu-Feng,Guo, Zhi-Hong,Coghi, Paolo,Monti, Diego
experimental part, p. 279 - 291 (2012/01/12)
Flavin adenine dinucleotide (FAD) is reduced by NADPH-E.coli flavin reductase (Fre) to FADH2 in aqueous buffer at pH7.4 under argon. Under the same conditions, FADH2 in turn cleanly reduces the antimalarial drug methylene blue (MB) to leucomethylene blue. The latter is rapidly re-oxidized by artemisinins, thus supporting the proposal that MB exerts its antimalarial activity, and synergizes the antimalarial action of artemisinins, by interfering with redox cycling involving NADPH reduction of flavin cofactors in parasite flavin disulfide reductases. Direct treatment of the FADH2 generated from NADPH-Fre-FAD by artemisinins and antimalaria-active tetraoxane and trioxolane structural analogues under physiological conditions at pH7.4 results in rapid reduction of the artemisinins, and efficient conversion of the peroxide structural analogues into ketone products. Comparison of the relative rates of FADH2 oxidation indicate optimal activity for the trioxolane. Therefore, the rate of intraparastic redox perturbation will be greatest for the trioxolane, and this may be significant in relation to its enhanced invitro antimalarial activities. 1HNMR spectroscopic studies using the BNAH-riboflavin (RF) model system indicate that the tetraoxane is capable of using both peroxide units in oxidizing the RFH2 generated insitu. Use of the NADPH-Fre-FAD catalytic system in the presence of artemisinin or tetraoxane confirms that the latter, in contrast to artemisinin, consumes two reducing equivalents of NADPH. None of the processes described herein requires the presence of ferrous iron. Ferric iron, given its propensity to oxidize reduced flavin cofactors, may play a role in enhancing oxidative stress within the malaria parasite, without requiring interaction with artemisinins or peroxide analogues. The NADPH-Fre-FAD system serves as a convenient mimic of flavin disulfide reductases that maintain redox homeostasis in the malaria parasite. Antimalarial peroxides and flavin reductase: NADPH-E.coli flavin reductase (Fre) reduces FAD to FADH2, which in turn rapidly reduces artemisinins and antimalarial peroxides to deoxy or ketone products under physiological conditions. Thus, antimalarial activity is due to perturbation of intraparasitic redox homeostasis by oxidation of FADH2 in critical flavoenzymes with consequent sequestration of NADPH. The tetraoxane uses both peroxide units in consuming two equivalents of NADPH in the NADPH-Fre-FAD system.
